The goals of this project are two-fold: to characterize severe chronic infections with Epstein Barr Virus (EBV) and other lymphoproliferative disorders, and to elucidate multiple aspects of the chronic fatigue syndrome which was, earlier, considered to be related to EBV infection. To date this research project has involved over 400 patients. Included are 10 patients who were diagnosed with severe chronic EBV infections on the basis of clinical, histological, molecular and serologic features. We continue to examine immunologic features of patients with severe chronic EBV-associated lymphoproliferation and explore treatments. Acyclovir, alpha and gamma interferons proved of little value, but immunosuppressive therapies are being used with good long-term results. Detailed virologic,immunologic, neurologic, endocrinologic, psychologic and therapeutic studies have been conducted in patients with chronic fatigue. To date, we still have no consistent laboratory abnormality that permits a clear diagnosis of the chronic fatigue syndrome. A series of earlier studies of the pituitary-adrenal suggested deficient central CRH release. Since CRH induces CNS arousal, these neuroendocrine findings suggest a new mechanism whereby the lethargy of Chronic Fatigue Syndrome patients may be explained. We verified these observations in a recent study in which Arginine-Vasopression infusions were given to CFS patients and controls to stimulate and test the HPA axis. We completed and are now analyzing the results of a placebo-controlled trial of hydrocortisone treatment designed to test the hypothesis that corticosteroid deficit leads to symptoms. We completed a study showing the absence of seasonality in CFS symptoms, further distinguishing it from Seasonal Affective Disorder. We completed a study of memory and a study of central fatigue using cortical magnetic stimulation. This past year we designed and initiated a placebo-controlled trial of fludricortisone for CFS in collaboration with scientists at Johns Hopkins. The trial is based on their original recognition of abnormal tilt-table responses in many CFS patients. Studies of exercise tolerance and hormonal responses to exercise are underway. A vigorous, multidisciplinary approach to the syndrome continues.